1. Field of the Invention
This invention relates to resuspendible, pharmaceutically elegant high concentration, low viscosity, aqueous antacid suspension dosage forms for oral administration and to methods for their preparation and use.
2. Decription of the Antacid Art
Antacids are widely used in the treatment of gastrointestinal disorders. Their effectiveness in promoting the healing of gastric and duodenal ulcers has been well documented. Essentially, antacids exert their positive effects by neutralizing the gastric acid secreted in the stomach. When the pH of stomach contents is raised above 3, most gastric acid is neutralized and the proteolytic activity of pepsin is inhibited. The recent elevation of antacids to a major therapeutic role, particularly in ulcer therapy, rather than a merely pallative role, has emphasized the importance of providing antacid products featuring a high neutralization (and buffer) capacity as well as a rapid rate of gastric acid neutralization. These features particularly that of rapid rate of neutralization to the neutralization capacity of the antacid define the more effective antacid in vivo since it is less likely that unconsumed antacids will be removed by normal gastric emptying.
Most antacids are available in both liquid and solid dosage forms. The liquid antacids, as aqueous suspensions, are, generally, more effective than the same antacids in solid dosage forms and are more commonly prescribed in the hospital. The greater effectiveness of liquid antacids is partially due to the large surface area available in liquid suspensions to react with gastric acid and partially due to the great amount of colloidal particles in aqueous suspension which can more easily reach the affected area where treatment is needed. Moreover, aqueous suspensions of undehydrated antacids are more reactive than dry or solid antacids.
While liquid antacids possess these advantages, the same require administration of relatively large volumes of liquid suspension. The ingestion of such large volumes is inconvenient, however, making the normal problem of assuring patient compliance outside the hospital environment even more difficult. Since high dose regimes of liquid antacid have recently been shown to be effective both in promoting the healing of duodenal ulcers and in preventing the acute upper gastrointestinal bleeding in critically ill patients, the use of regular liquid antacid suspensions with the usual solid antacid content in the 6-12 percent range has become even more impractical for such therapeutic indications.
The most widely used antacids can be described as mineral type, insoluble inorganic salts that are hydrated, possess colloidal properties, and contain, for example, aluminum, magnesium, bismouth and the like. Compounds of the described mineral variety in their freshly prepared, hydrated form and in suspensions therefrom provide some of the characteristics desired in an antacid. To provide liquid antacids with a high neutralization capacity it is necessary to increase the solids concentration of the antacid components. Such increases in concentration, however, are accompanied at higher levels with exponential increases in viscosity, a loss in colloidal properties and a loss of fluidity or mobility. Even where fluidity is initially maintained or achieved, further requirements of pharmaceutically acceptable aqueous antacid suspensions call for a smooth (non-gritty) mouth feel and maintenance of a gel structure for both suspendibility and resuspendibility. In general, resuspendible, aqueous antacid suspensions are typically de-flocculated products which contain a deflocculant or suspending agent to arrest or control further agglomeration or flocculation and settling. In the absence of a deflocculant or suspending agent type additive, the antacid in a suspension forms a hard cake or a gel structure which can no longer be resuspended with its original desirable characteristics. The formation of such a cake or gel structure is independent of antacid concentration except for low antacid concentration.
The deflocculants and suspending agents have been frequently included in the formulation of aqueous antacid suspensions containing solid antacid concentrations in the range of about 6 to 12 percent to prevent caking. With the growing interest in providing antacid suspension dosage forms with a greater acid neutralizing capacity, means were sought to provide highly concentrated but fluid systems.
U.S. Pat. No. 3,579,634 describes an antacid composition containing as the essential ingredients an antacid and a water dispersible, colloidal anionic ether or ester derivative of a low polymer of a monosaccharide as a gelation agent, the gelation agent being such that a thickened gel-like consistency occurs upon interaction of the composition with gastro-intestinal mucous so as to adhere thereto. The gelation agent in vitro is described as providing fluidity to concentrated suspensions, and the starting actacid may be selected from powder, granule or paste forms of certain calcium, aluminum, magnesium, sodium and bismouth antacids. The antacid suspension compositions disclosed therein appear to initially require milling, high energy agitation or homogenization to eliminate the grittiness of the antacid ingredient.
In U.S. Pat. No. 3,591,680, high concentration antacid suspensions are disclosed containing about 25 to 50 percent weight/volume of certain selected solid antacid materials suspended in an aqueous vehicle containing certain specified suspending agents of which a defind hydroxypropyl cellulose is preferred. While these suspension are said to provide stable and palatable, high concentration suspensions, the preferred composition is stated to provide only a minimum of 2 months of continued fluidity and pourability. Such standards are not acceptable for a commercial product in which shelf life stability should extend for at least 1-2 years.
U.S. Pat. No. 3,347,744 discloses a high concentration magnesium hydroxide suspension containing up to 30% of that antacid with a cellulosic suspending agent and submicroscopic silica. The suspension is said to avoid the clumping and caking common among even lower concentration magnesium hydroxide suspensions, although there is no disclosure that the suspension is thereby rendered more fluid.
More recently, in U.S. Pat. No. 4,117,116, there is disclosed a method for lowering the viscosity of a commercially available aqueous antacid gel cake to render the same pumpable in the production environment. The gel cake represents a magnesium hydroxide antacid, an aluminum hydroxide antacid or a mixture thereof and the antacid is 25-35% weight by weight of the gel cake before processing. The method comprises mixing into the gel cake a fluidizing agent selected from acacia, citric acid, sodium citrate, sodium lauryl sulfate or dioctyl sodium sulfosuccinate and the fluidizing agent amounts to 0.1-4% of the final total mixture.
It is an object of this invention to provide magaldrate, aqueous antacid suspensions with high antacid capacity and good mouth feel characteristics.
Another object of this invention is to provide magaldrate, aqueous antacid suspensions with high antacid capacity and which retain, at high concentrations, the desirable qualities of rapid acid neutralization and reliably uniform reaction in acidic solutions.
A further object of the invention is to provide high antacid capacity, aqueous magaldrate suspensions with good fluidity, pourability and suspension characteristics and which further provides full resuspendibility under the typical shelf life conditions for a commercial aqueous antacid suspension.